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Compound having detrusor muscle-contracting activity and urethral sphincter muscle-relaxing activity

a technology of urethral sphincter and detrusor muscle, which is applied in the field of compound having detrusor muscle contracting activity and relaxing activity of urethral sphincter, can solve the problems of insufficient clinical application effect and expression of side effects in organs, and achieve the effects of reducing the risk of urethral sphincter dysfunction, preventing and/or treating underactive bladder, and reducing the risk of urethral s

Active Publication Date: 2013-04-02
ONO PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention relates to a new compound that has the ability to contract the bladder and relax the urethra. This compound can be used to treat bladder and urethra dysfunctions such as bladder contraction and urethral relaxation. It has minimal side effects on the kidneys, heart, and digestive system and is stable against hepatic metabolism, which allows for sustained drug efficacy. This compound has good membrane permeability and oral absorbability.

Problems solved by technology

Since cholinergic agents, acetylcholinesterase inhibitors and al receptor antagonists, which have been used for the treatment of underactive bladder, have only either of an activity for enhancing the contractility of the bladder detrusor or an activity for relaxing the urethral sphincter as the mechanisms of action thereof, they exhibit insufficient effects in terms of clinical application.
Furthermore, since the drugs act on the autonomic nervous system, there has been pointed out the expression of side effects in organs other than the bladder.

Method used

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  • Compound having detrusor muscle-contracting activity and urethral sphincter muscle-relaxing activity
  • Compound having detrusor muscle-contracting activity and urethral sphincter muscle-relaxing activity
  • Compound having detrusor muscle-contracting activity and urethral sphincter muscle-relaxing activity

Examples

Experimental program
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Effect test

examples

[0157]The present invention will be explained in detail by Examples. However, the present invention is not limited by the Examples.

[0158]The solvents in the parenthesis indicated in the separated portion by the chromatography and TLC represent eluting or developing solvents used and their ratio is volume ratio.

[0159]NMR data are 1H-NMR data in 300 MHz unless otherwise specified. The parentheses in the NMR data represent solvents used for measurement.

[0160]The compounds used herein were named by a computer program which names chemical names according to the IUPAC rules, ACD / Name Batch (registered trademark), or according to IUPAC nomenclature. For example,

[0161]

was named as 2-[(2-{((1R,5R)-2-oxo-5-[(1E,4S)-7,8,8-trifluoro-4-hydroxy-4-methyl-1,7-octadien-1-yl]cyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylic acid.

preparation examples

Example 1

4,5,5-trifluoro-N-methoxy-N-methyl-4-penteneamide (Compound 1)

[0162]N,O-dimethylhydroxyamine hydrochloride (3.5 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.9 g) and triethylamine (9.2 mL) were added to a solution of 4,5,5-trifluoropent-4-enoic acid (CAS No. 110003-22-0 (5.0 g)) in methylene chloride solution (64 mL) in a cold-water bath and stirring was carried out at room temperature overnight. The reaction solution was concentrated and diluted with ethyl acetate. The dilute solution was washed with 1 N hydrochloric acid, water and saturated brine; dried with anhydrous sodium sulfate; and concentrated to obtain the title compound (6.4 g) having the following physical properties:

[0163]TLC: Rf 0.50 (ethyl acetate:hexane=1:2);

[0164]NMR (CDCl3): δ 2.51-2.77 (m, 4H), 3.19 (s, 3H), 3.69 (s, 3H).

example 2

Ethyl 6,7,7-trifluoro-3-oxo-6-heptenoate (Compound 2)

[0165]Ethyl acetate (4.8 mL) was slowly added dropwise to a lithium hexamethyldisilazide / tetrahydrofuran solution (1 M, 48 mL) at −78° C., followed by stirring for 30 min. The solution of compound 1 (6.4 g) in anhydrous tetrahydrofuran (33 mL) was slowly added dropwise to the reaction solution at the same temperature followed by stirring for 30 min. To the reaction solution, 2 N hydrochloric acid (30 mL) was added, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine; dried with anhydrous sodium sulfate; and concentrated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1→15:1) to obtain the title compound (4.94 g) having the following physical properties:

[0166]TLC: Rf 0.63 (ethyl acetate:hexane=1:2);

[0167]NMR (CDCl3): δ 1.29 (t, J=7.1 Hz, 3H), 2.50-2.71 (m, 2H), 2.83 (t, J=7.2 Hz, 2H), 3.47 (s, 2H), 4.21 (q, 2H).

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Abstract

Since a compound represented by formula (I) wherein all of the symbols are the same as defined in the specification, a salt thereof, a solvate thereof, a prodrug thereof, a mixture with a diastereomer thereof in an arbitrary ratio, or a cyclodextrin clathrate thereof have a contracting activity of bladder detrusor and a relaxing activity of urethral sphincter, they can ameliorate bladder contraction dysfunction and / or urethral relaxation dysfunction, and for example, are effective for underactive bladder. Additionally, the compound of the present invention has little risk of side effects on the urinary system, the circulatory system and the digestive system, and exhibits excellent pharmacokinetics, such as oral absorbability etc. Therefore, the compound of the present invention is useful as a superior agent for preventing, treating and / or ameliorating underactive bladder.

Description

TECHNICAL FIELD[0001]The present invention relates to a compound having a contracting activity of bladder detrusor and a relaxing activity of urethral sphincter, represented by formula (I):[0002][0003]wherein all of the symbols have the same meanings as defined below, a salt thereof, a solvate thereof, a prodrug thereof, a mixture with a diastereomer thereof in an arbitrary ratio, or a cyclodextrin clathrate thereof (hereinafter, the compound represented by formula (I), the salt thereof, the solvate thereof, the prodrug thereof, the mixture with a diastereomer thereof in an arbitrary ratio, or the cyclodextrin clathrate thereof is also referred to simply as “compound of the present invention”). The present invention also relates to a pharmaceutical composition comprising the compound of the present invention as an active ingredient.BACKGROUND ART[0004]With regard to a symptom wherein bladder cannot be empty (incomplete bladder emptying) resulting from insufficient micturition contra...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): A61K31/426C07D277/56
CPCA61K31/426A61K47/48969B82Y5/00A61K45/06C07D277/36C07D277/56C08B37/00C07D277/20A61K47/6951A61P13/02A61P13/10A61P43/00A61K47/50A61K45/00A61K47/40C07D277/26
Inventor OHMOTO, KAZUYUKIKINOSHITA, AKIHIROMATSUYA, HIDEKAZUOKADA, HIROKI
Owner ONO PHARMA CO LTD
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